1. Field of the Invention
The present invention relates to pharmaceutical compositions, in particular oral dosage forms for rhinitis comprising a combination of decongestant and antihistamine.
2. Background
Rhinitis refers to an inflammatory disorder of the nasal passages. The symptoms of rhinitis typically consist of sneezing, rhinorrhea, nasal congestion, and increased nasal secretions. Failure of treatment of rhinitis may lead to other disorders that include infection of the sinuses, ears, and lower respiratory tract. Two types of oral medication are commonly used to treat the symptoms of rhinitis, decongestants and antihistamines. Decongestants and antihistamines differ in their mechanisms of action, therapeutic effects, and side effects. It is common practice to combine both of these medications to bring about more complete symptom relief of rhinitis than with either entity alone.
Decongestants commonly used to treat rhinitis include the adrenaline-like agents pseudoephedrine and phenylpropanolamine. These agents act to constrict vessels in the nasal mucus membranes and thereby decrease tissue swelling and nasal congestion. Decongestants are found to be better than antihistamines for restoring the patency of congested nasal airways. Like adrenaline, nasal decongestants are stimulatory and produce side effects that may be tolerated while the user is awake, and may even be considered desirable to counter fatigue that is known to accompany other symptoms of rhinitis. Decongestants, however, may produce nervousness, restlessness, and insomnia if taken when sleep is desired. This can be a source of confusion for individuals, who mistakenly attribute their inability to sleep to the malaise that may accompany other rhinitis symptoms, rather than to the decongestant medication.
Histamine is a mediator released from cells that line the walls of the nasal mucous membranes (mast cells). When released, histamine binds to local histamine receptors causing sneezing, nasal itching, swelling of the nasal membranes, and increased nasal secretions. Antihistamines relieve these effects, albeit by a different mechanism than decongestants. Antihistamines block the binding of histamines to the histamine receptors by preemptively binding to the receptors. Consequently they are effective only if given prior to histamine release since once histamine is released and binds to the receptors, it is too late. Although individuals typically take antihistamines after symptoms occur, it is more desirable to dose antihistamines so as to effect therapeutic availability in anticipation of histamine release. Antihistamines are generally sedating. However, newer antihistamines with no or little sedation have been developed in the last twenty years.
Combining decongestants and antihistamines utilizes both mechanistic approaches, and has been shown to offer more complete relief of rhinitis symptoms than therapy with either component alone. Consequently, many products have been formulated so that their dosage units contain both. The incorporation of decongestant and sedating antihistamine into a single dosage unit attempts a balance between the stimulating and sedating side effects of these components.
However, individuals are known to vary in their susceptibility to these side effects. Consequently, some individuals experience sedation when taking these combinations during the day or stimulation and insomnia when taking the combinations at night. More recently, formulations have been commercialized which incorporate a decongestant and a non-sedating antihistamine into a single dosage unit for the purpose of avoiding daytime sedation. Such combinations might be expected to provoke a greater incidence of nighttime irritability and insomnia because the stimulating side effects of decongestant are not attenuated by concomitant sedation by antihistamine. Indeed, a 25% incidence of insomnia has been disclosed among users of a commercialized combination of the non-sedating antihistamine terfenadine and the decongestant pseudoephedrine. Examples of such formulations include:
SELDANE-D(copyright) Extended-Release Tablets which contains 60 mg terfenadine (non-sedating antihistamine) and 120 mg pseudoephedrine hydrochloride (stimulating decongestant), and which is recommended to be taken every 12 hours (adults and children over 12 years of age).
ALLEGRA-D(copyright) contains 60 mg fexofenadine (non-sedating antihistamine) and 120 mg pseudoephedrine hydrochloride (stimulating decongestant), and which is recommended to be taken every 12 hours (adults and children over 12 years of age).
CLARITIN-D(copyright) 24-HOUR Extended-Release Tablets which contains 10 mg loratidine (non-sedating antihistamine) and 240 mg pseudoephedrine hydrochloride (stimulating decongestant), and which is recommended to be taken every 24 hours (adults and children over 12 years of age).
These and all currently marketed single entity combinations, which are formulated with decongestant and antihistamine, fail to address the problem of nighttime irritability and insomnia, a problem that is increased by combining non-sedating, rather than sedating antihistamine. Note is made of prior art which is directed toward reducing the side effects of antihistamines and decongestants. U.S. Pat. No. 4,295,567, issued to Knudsen, teaches a regimen for employing separate day and night dosage units for the purpose of avoiding daytime sedation from sedating antihistamines. This patent does not anticipate the advent of non-sedating antihistamine and overlooks the side effect of nighttime stimulation from decongestants. A regimen, commercialized as SYN-RX(trademark), also employs separate day and night dosage units. SYN-RX(trademark) contains a daytime formulation of 600 mg guaifenesin, which is non-stimulating, and 60 mg pseudoephedrine, which is stimulating, and a nighttime formulation of 600 mg of guaifenesin alone. SYN-RX(trademark) does not contain an antihistamine. In failing to contain any medication that would be effective for the common symptoms of rhinitis at night, SYN-RX(trademark) does not constitute a treatment for rhinitis. The use of multi-dosage unit regimens of such prior art is less convenient for a user than a single dose, once-per-day formulation, and more complex to follow, adding the potential for a user to confuse dosage units.
Individuals with rhinitis utilize antihistamines and decongestants together many of millions of times a year. Professional as well as consumer confusion is widely encountered with the use of these medications together, and unnecessarily negative consequences occur both by self-selection and prescription. In particular, individuals treated with decongestants at night not only risk insomnia, but also daytime irritability, fatigue, and malaise from lack of rest. It is known that these side effects are sometimes mistakenly ascribed to rhinitis rather than to the medication causing them. There is a present need for formulations which circumvent this confusion and which avoid nighttime stimulation.
It is an object of the present invention to simplify the combined use of antihistamine and nasal decongestant medications to enhance convenience, reduce patient errors and minimize side effects of the combined medications. The formulation of the invention can be taken once per day and avoids stimulation at night.
In one aspect the invention relates to oral dosage units comprising: (a) an antihistamine in an amount and formulation to exhibit antihistaminic activity in a human for greater than 22 hours; and (b) a decongestant in an amount and formulation to exhibit stimulatory activity in a human for less than 16 hours. The decongestant amount and formulation may also exhibit decongestant activity in a human for less than 16 hours.
In a closely related aspect, the invention relates to oral dosage units in which the decongestant is formulated to release decongestant non-linearly, such that discontinuity of release occurs between 12 and 16 hours and some portion of decongestant is released beyond 12 hours. To the extent that decongesting activity can be separated from stimulatory activity by control of serum concentration of the decongestant, it may be advantageous to maintain a lower, but decongestively effective serum concentration beyond 12 hours.
As noted, individuals are known to vary in their susceptability to the stimulating side effects of decongestants, and it is an important object of the present invention to provide a formulation in which such stimulation is minimized or absent in the 16-24 hour period after dosing in most individuals, in contrast to the stimulatory activity found to interfere with sleep in 25% of individuals taking present decongestant-non-sedating antihistamine formulations.
In another aspect, the invention relates to a method of providing treatment for rhinitis in a human comprising: (a) formulating an amount of an antihistamine to exhibit antihistaminic activity in a human for greater than 22 hours; (b) formulating an amount of a decongestant to exhibit stimulatory activity in a human for less than 16 hours; (c) combining the antihistamine and the decongestant in a single oral dosage unit; and (d) providing instructions to administer the oral dosage unit at the start of the day.
In another aspect, the invention relates to a kit, which provides a once-per-day dosage regimen for treating rhinitis, while avoiding stimulation at night. The kit comprises: (a) an oral dosage form containing an amount of an antihistamine to exhibit antihistaminic activity in a human for greater than 22 hours; (b) an oral dosage form containing an amount of a decongestant to exhibit stimulatory activity in a human for less than 16 hours; and (c) instructions to administer the antihistamine and decongestant at the start of the day. The antihistamine and the decongestant may be in separate dosage units or may be combined in a single oral dosage unit.
The single dosage unit of the present invention for treating the symptoms of rhinitis may additionally include other medications, such as an analgesic.